Abstract

Prolonged or uncontrolled B-cell receptor (BCR) signaling is associated with autoimmunity. We previously demonstrated a role for actin in BCR signal attenuation. This study reveals that Actin-binding protein 1 (Abp1/HIP-55/SH3P7) is a critical negative regulator of BCR signaling, and is responsible for linking actin remodeling to negative regulatory pathways of the BCR. In Abp1 knockout mice, the numbers of spontaneous germinal center B cells and marginal zone B cells are significantly increased, while early B-cell development is unaltered. Serum levels of autoantibody and total antibody are elevated, while T-dependent antibody responses are markedly reduced. Upon activation, surface BCR clustering is enhanced and B-cell contraction is delayed in Abp1-/- B cells; concurrent with slow but persistent increases in F-actin at BCR signalosomes. Furthermore, BCR signaling is enhanced in Abp1-/- B cells compared to wild-type B cells, including increased levels of Ca2+ flux and phosphorylated BLNK, MEK1/2 and ERK, coinciding with reductions in the recruitment of the inhibitory signaling molecules HPK1 and SHIP-1 to BCR signalosomes. Our results indicate that Abp1 contributes to the maintenance of B-cell tolerance via negatively regulating BCR signaling, by promoting actin-dependent B-cell contraction and activation of inhibitory signaling molecules. This reveals a new mechanism for negative regulation of BCR signaling.